Abstract: FR-PO333
Methionine Restriction Prevents Cystine Urolithiasis in a Mouse Model of Cystinuria
Session Information
- Genetic Diseases: Models, Mechanisms, Treatments
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1102 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Perreault, Mylene, Synlogic, Cambridge, Massachusetts, United States
- Sahota, Amrik, Rutgers The State University of New Jersey, New Brunswick, New Jersey, United States
- Yang, Min, Rutgers The State University of New Jersey, New Brunswick, New Jersey, United States
- Tischfield, Jay A., Rutgers The State University of New Jersey, New Brunswick, New Jersey, United States
- Xu, Julia, Synlogic, Cambridge, Massachusetts, United States
- Hava, David, Synlogic, Cambridge, Massachusetts, United States
Background
Cystinuria is an inherited metabolic disorder caused by mutations in the SLC3A1 and/or SLC7A9 genes responsible for cystine reabsorption in the kidney. Defects in either of these genes is characterized by excessive excretion of cystine in the urine, which can result in the formation of crystals and/or stones in the kidney or bladder. Cystine is formed by the binding of two cysteine molecules, and strategies that aim at reducing cystine concentration in urine are recommended and include increased fluid intake, urine alkalization, and a reduction in protein intake enriched in cysteine and methionine. In mammals, the transsulfuration pathway is the only cysteine biosynthesis route and it requires the essential amino acid methionine. SYNB1353 is an engineered strain of E. coli Nissle that metabolizes methionine in the gastrointestinal (GI) tract and prevents its absorption. To determine whether the metabolism of methionine in the GI tract could lower cystine levels and hence prevent stone formation, we assessed the impact of dietary methionine restriction in the Slc3a1 knockout (KO) mouse model of cystinuria.
Methods
Six weeks old male Slc3a1 KO mice were provided with regular (0.62%) or low (0.12%) methionine diets for 8 weeks. Body weight and food intake were measured weekly, urine collected every 2 weeks, and bladder stone volume was determined every 2 weeks by computed tomography (CT) scan. At the end of the experiment, bladders were dissected, and stones removed and weighed.
Results
In Slc3a1 KO mice, methionine restriction caused 39% body weight loss, whereas mice maintained on regular diet gained 7% of their initial body weight. Bladder stones were detected by CT scan in 7 of the 12 KO mice on regular diet, with the onset of stone detection ranging from 2 to 8 weeks of dietary treatment. However, bladder stones were not detected in mice fed the low methionine diet. Following bladder dissection, stones were identified in 2 additional mice on regular diet, with bladder and stone weights in the 9 mice ranging from 13.9-82.1 mg and 0.2-83.3 mg, respectively. Bladder weight in 12 mice maintained on low methionine diet averaged 5.7-11.0 mg.
Conclusion
Overall, these data indicate that methionine restriction prevents stone formation in Slc3a1 KO mice and SYNB1353 may offer a viable approach for the treatment of cystinuria.
Funding
- Commercial Support –